A group of novel phosphatidyl inositol (PI) analogs are found to be effective phospholipase C inhibitors which are useful anti-inflammatory and analgesic agents.
Phospholipase C contained in mouse peritoneal macrophages has been linked to the enhanced turnover of phosphatidyl inositols which in turn has been suggested by recent studies as one of the sources of arachidonic acid. It has been established that a rapid synthesis of prostaglandins (PG) from arachidonic acid in macrophages usually accompanies inflammatory stimuli. Thus, inhibition of the release of arachidonic acid from macrophages would provide an effective control of PG synthesis and thereby inflammatory conditions. Recently, phospholipase C has been characterized as an enzyme which is involved in the biosynthetic phosphatidylinositol-arachidonic acid-prostaglandin pathway. This finding is further substantiated by the observation that phospholipase C is inhibited by phenothiazine, a compound known to inhibit the stimulated release of arachidonic acid from macrophages and prostaglandins from platelets.
Accordingly, it is an object of this invention is provide specific and selective inhibitors of phospholipase C which can be potent anti-inflammatory and analgesic agents useful in the treatment of inflammatory conditions, including rheumatoid arthritis, emphysema, bronchial inflammation, osteoarthritis, spondylitis, lupus, psoriasis, acute respiratory distress syndrome, gout, fever, and pain.
Another object of this invention is to provide pharmaceutical compositions to be used in the administration of the novel phospholipase C inhibitors, which are novel phosphatidyl inositol analogs.
Still a further object of this invention is to provide a method of controlling and treating inflammation and pain by administering an effective amount of the novel phosphatidyl inositol analogs in a mammalian species in need of such treatment.
Finally, it is also an object of this invention to provide a process for preparing the novel phosphatidyl inositol analogs.